1. Technology Field
The present invention relates to cell-based vaccines, and more particularly, to vaccines and methods of using same, wherein the vaccines are based on tumor cells from immune-privileged sites that have the ability to activate immunity against the originating tumor cells as well as against metastatic tumor cells.
2. Related Art
Immunotherapy is a potential approach for the treatment and/or prevention of cancer because of its specificity, sensitivity, potency, and long-term memory. Induction of a T lymphocyte response is a critical initial step in a host's immune response. Activation of T cells results in T cell proliferation, cytokine production by T cells and generation of T cell-mediated effector functions. T cell activation requires an antigen-specific signal, often called a primary activation signal, which results from stimulation of a clonally-distributed T cell receptor (hereafter TcR) present on the surface of the T cell. This antigen-specific signal is usually in the form of an antigenic peptide bound either to a major histocompatibility complex (hereafter MHC) class I protein or an MHC class II protein present on the surface of an antigen presenting cell (hereafter APC). CD4+ T cells recognize peptides associated with class II molecules. Class II molecules are found on a limited number of cell types, primarily B cells, monocytes/macrophages and dendritic cells, and, in most cases, present peptides derived from proteins taken up from the extracellular environment. In contrast, CD8+ T cells recognize peptides associated with class I molecules. Class I molecules are found on almost all cell types and, in most cases, present peptides derived from endogenously synthesized proteins.
Notably, CD4+ T lymphocytes long have been recognized by tumor immunologists as critical elements for priming tumor-specific CD8+ T cells. They also are required for effective immunity during chronic infections, a scenario similar to prolonged tumor growth and progression. T cells that are cytotoxic for tumor cells are typically CD8+ T lymphocytes, and optimal activation of these cells usually requires coactivation of CD4+ T helper lymphocytes. CD4+ T lymphocytes are also required for generating CD8+ T memory cells.
Primary ocular or uveal melanoma is the most common malignancy of the eye and can be effectively treated with a variety of therapies, such as plaque radiotherapy, laser photocoagulation, transpupillary thermotherapy, trans-scleral resection, or enucleation of the tumor-bearing eye. Although these treatments limit the growth of the primary tumor and may partially preserve vision, they do not prevent the development of metastases, which occurs in ˜50% of patients with large tumors (1-3) and is universally fatal within ˜4 to 9 months of diagnosis (4). Although several treatments are available that increase median survival time to ˜15 months, metastatic uveal melanoma remains universally fatal (5,6).
Thus it would be advantageous to develop cell-based tumor vaccines that are effective at activating both CD4+ and CD8+ T lymphocytes to induce antitumor immunity in patients with tumor producing diseases and also provide immunity that is cross-reactive with other types of metastatic tumors.